3-Hydroxy-4-pyridinones are bidentate ligands that chelate to the Fe(III) ion in the ratio of 3:1 and are useful in the removal of excess body iron in humans. Iron overload may be due to excess dietary consumption of iron, inherited genetic conditions such as haemochromatosis and regular blood transfusion. Such transfusions are used to treat medical conditions such as thalassaemia, sickle cell anaemia, idiopathic haemochromatosis and aplastic anaemia. Increased iron absorption from transfusion leads to iron overload. Upon saturation of ferritin and transferrin in the body, iron deposit in many tissues such as the myocardium, liver and endocrine organs resulting in toxic effects.
The scope of iron chelator research and the proposed utility of chelators have been reviewed (Current Medicinal Chemistry, 2003, 10, 983-985, Tim F. Tam, et al). Iron chelators may be useful to prevent hydroxy radical formation, treatment of cancer, malaria, post-ischaemic reperfusion, and neurodegenerative diseases. Iron chelators such as Desferal™ (desferrioxamine mesylate) and Ferriprox™ (deferiprone) are used to remove excess body iron in thalassemia major patients because the human body has no effective means to excrete the iron accumulated from blood transfusion. Desferrioxamine is administered daily by subcutaneous infusion over a period of 8 to 12 hours. At present, deferiprone (1,2-dimethyl-3-hydroxy-4-pyridinone) is the only orally drug available. It undergoes extensive metabolism in the liver and more than 85% of the administered dose is recovered in the urine as the non-chelating O-glucuronide (Drug Metab. Dispo. 1992, 20(2), 256-261, S. Singh, et al.). A relatively high oral dose of 75 mg/kg (3.5 to 4 gm per day) is required for the treatment of iron overload conditions. Therefore, there is a need to identify a new orally active hydroxypyridinone with improved pharmacological properties than deferiprone.
Voest et. al. (Annals of Internal Medicine 1994, 120, 490-499) reviewed the clinical experience of iron chelators in non-iron overloaded conditions. Iron chelators were used to produce antioxidant effects, antiproliferative effects, antiprotozal effects and for aluminum chelation, and may be used be for a variety of disease state such as the treatment of rheumatoid arthritis, the protection against anthracycline cardiac poisoning, for limiting mycocardial ischemia-reperfusion injury, as antitumour agents, and for the treatment of malaria. In addition, van Asbeck B. S. et. al. (J Clin Virol. 2001 February;20(3):141-7) reported that iron chelators have anti-HIV activities. Therefore the utitlies of iron chelators are not only restricted to the treatment of iron-overloaded conditions.
The members of the 3-hydroxy-4-pyridinones class are known for their ability to chelate iron. Prior art includes RE 35,948, U.S. Pat. Nos. 6,448,273, 6,335,353 and 5,480,894. In U.S. Pat. No. 6,335,353, the ester prodrug derivatives of 3-hydroxy-4-pyridinones are used to facilitate efficient iron extraction from the liver, however none of the designed compounds has reached evaluation in humans.
In other approaches, selected new compounds were designed to block the phase II metabolism of O-glucuronidation at the C3 oxygen of the deferiprone skeleton. U.S. Pat. No. 5,688,815 reported 1-alkyl-3-hydroxy-4-pyrdinones with a C2 methyl group substituted with a phenyl or heteroyl ring and a hydroxy group, and the N1 substituent being a lower alkyl. U.S. Pat. No. 6,335,353 described 1-alkyl-3-hydroxy-4-pyridinone with a C2 alkylcarbamoyl, arylcarbamoyl, or an aralkylcarbamoyl group and the N1-substituent is an aliphatic hydrocarbon group. The use of C2-methylcarbamoyl functionality in compound such as CP502 (1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-methyl)-amide hydrochloride; U.S. Pat. No. 6,335,353) effectively blocked the O-glucuronidation at the C3 oxygen. Other analogues in U.S. Pat. No. 6,335,353 include CP506 (1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N-isopropyl)-amide hydrochloride), the C2-isopropylcarbamoyl analogue and CP508 (1,6-Dimethyl-3-hydroxy-4(1H)-pyridinone-2-carboxy-(N,N-dimethyl)-amide hydrochloride), the dimethylcarbamoyl analogue. CP502, CP506 and CP508 are prior art and have not been evaluated in humans.